Sodium enalapril complex and the use thereof to make sodium enalapril

ABSTRACT

A process for making pure sodium enalapril is provided which includes the step of decomplexing essentially pure sodium enalapril-sodium iodide complex to yield essentially pure sodium enalapril.

This application is a divisional of application Ser. No. 08/699,338filed Aug. 19, 1996, now U.S. Pat. No. 5,637,730.

FIELD OF THE INVENTION

This invention relates to a process for making pure and stable sodiumenalapril-sodium iodide complex which can be decomplexed to give puresodium enalapril. This invention also relates to other sodium enalaprilmonovalent metal monovalent counterion complexes which can also bedecomplexed to give pure sodium enalapril.

BACKGROUND OF THE INVENTION

Enalapril is a well-known ACE inhibitor. Its chemistry (Medicinal Chem.Rev., 1985, 5, 483), preparation (U.S. Pat. No. 4,374,829), biologicaltransport (Advanced Drug Delivery Rev., 1992, 8, 253), activemetabolites (Drug Met. Dispos., 1982, 10, 15). Pharmacology (J.Pharmacol. Exp. Ther,. 1981, 216, 552), Bioavailability (J. Pharmacol.Exp. Ther., 1983, 226, 192), and clinical use in the treatment ofhypertension have been reviewed.

Enalapril is typically isolated and purified as the maleate additionsalt. Another salt of enalapril which could have pharmaceuticallyacceptable characteristics is the sodium salt. The sodium salt ofenalapril is not easily purified since it is soluble in most organicsolvents and in water. In pure form, it is a hydroscopic oil or glass.Sodium enalapril can be prepared by treating the maleate with a sodiumalkoxide or sodium hydroxide and selectively crystallizing the disodiumsalt of maleic acid. The solutions containing pure sodium enalapril thusobtained often contain trace amount of the base used to form the salt.Sodium enalapril undergoes a very facile ester hydrolysis in aqueousmedia in the presence of base to generate sodium enalaprilat, which isnot orally active. Commercial production of pure sodium enalapril isthus very difficult.

It is therefore an object of this invention to provide improvedprocesses for the manufacture of sodium enalapril and intermediatesthereof.

It is a further object to provide intermediates suitable for use tomanufacture sodium enalapril.

Further and other objects of the invention will be realized by thoseskilled in the art from the following summary of the invention anddetailed description of embodiment.

SUMMARY OF INVENTION

During our attempts to make sodium enalapril, conditions which wouldminimize trace amounts of strong bases and organic media most likely tofacilitate the precipitation of a sodium salt were investigated. One ofthese approaches involved the formation of the tetrabutylammonium saltof enalapril which was then treated with sodium iodide. The resultingmixture underwent an ion exchange and a precipitate was formed. Theresulting precipitate was not the expected sodium enalapril butsurprisingly a sodium iodide-sodium enalapril complex. The complex canthen be purified by recrystallization and handled easily. The puresodium iodide complex of sodium enalapril is then decomplexed by forexample an ion exchange with tetraalkylammonium chlorides and subsequentselective precipitation of the sodium chloride and tetraalkylammoniumiodide. The sodium iodide-sodium enalapril complex thus provides amethod of obtaining pure sodium enalapril under very mild conditionseasily carried out on a commercial scale.

Thus according to one aspect of the invention, a process for making puresodium enalapril includes (comprises) the step of decomplexingessentially pure sodium enalapril-sodium iodide complex to yieldessentially pure sodium enalapril. (IIIA) According to another aspect ofthe invention, the manufacture of the sodium enalapril-sodium iodidecomplex comprises reacting crude sodium enalapril with sodium iodide toyield the sodium enalapril-sodium iodide complex. This complex can beeasily purified.

The purified sodium enalapril-sodium iodide complex can then bedecomplexed to produce the pure sodium enalapril, for example in anorganic solution.

The sodium enalapril can be made by reacting I with1,1'-carbonyldiimidazole (CDI) to form anhydride (II) which is reactedwith the sodium salt of L-Proline to produce crude sodium enalapril III.##STR1##

Crude enalapril III may react with sodium iodide to produce essentiallypure sodium enalapril iodide complex (IV). The decomplexation of theessentially pure sodium enalapril-sodium iodide complex (IV) may beaccomplished by ##STR2##

The sodium enalapril-sodium iodide complex (IV) has been found to be thepreferred compound for this reaction. However, other complexes as wouldbe apparent to persons skilled in the art are meant to be incorporatedin this process. Such complexes would be manufactured in accordance withthe teachings herein appropriately modified to make the desired complex.

DETAILED DESCRIPTION OF THE EMBODIMENTS

An Embodiment provides a new method for the production of sodiumenalapril. (S)-N-(1-Ethoxycarbonyl-3-phenylpropyl)-L-alanine (I) isreacted with 1,1'-carbonyldiimidazole (CDI) to form the anhydride (II)which is reacted in an aprotic solvent with the sodium salt of prolineto afford crude sodium enalapril (III) (75% yield).

Purification of the crude sodium enalapril (III) is convenientlyachieved by the addition of one equivalent mole of sodium iodide to asolution of crude sodium enalapril in an alcohol such as ethanol orisopropanol which results in the formation of a 1:1 complex of sodiumenalapril-sodium iodide (IV) for which is only slightly soluble in thealcohol used. Excess sodium iodide, as well as impurities associatedwith the synthesis of sodium enalapril, will remain dissolved in thealcohol and the pure solid complex ((IV) greater than (99%) purity), maybe separated by filtration. Final purification of the complex isachieved by recrystallization from the alcohol used or a water-alcoholmixture. ##STR3##

Quantitative removal of sodium iodide from the complex can be achievedin a heterogeneous mixture of solvents consisting of a hydrophobicsolvent such as toluene and a protic solvent such as water. The latteris removed by azeotropic distillation, causing precipitation, forexample of tetramethylammonium iodide and sodium chloride. Sodiumenalapril remains dissolved in toluene and can be separated fromprecipitated salts by filtration, resulting in a clear solution thatcontains the pure sodium enalapril. Although other tetraalkylammoniumchlorides and other compounds as would be understood herein by personsskilled in the art may be used as well, the use of tetramethylammoniumchloride is preferred since the resulting salts, namelytetramethylammonium iodide and sodium chloride, are very insoluble inhydrocarbon solvents.

Enalapril maleate is a very stable solid at room temperature, less than2% degradation can be induced by storage at 80° C. for three weeks(Analytical Profiles of Drug Substances, 1987,16, 207). The sodiumenalaprillsodium iodide complex is also a stable solid at roomtemperature. HPLC analysis indicates less than 0.5% degradation bystorage at 80° C. for three weeks.

A 1 mg/mL aqueous solution of sodium enalapril obtained by decomplextionof the sodium iodide complex generates less than 0.2% enalaprilat after4 hours at room temperature.

EXAMPLE 1 Sodium Enalapril.Sodium Iodide Complex

(S)-N- 1-(S)-ethoxycarbonyl-3-phenylpropyl!-L- alanine (60 g, 0.215 mol)is suspended in 470 mL ethyl acetate and treated with1,1'-carbonyldiimidazole (41.85 g, 0.258 mol). The mixture was stirredat room temperature for 1 hour. Sodium salt of L-Proline (29.46 g, 0.215mol) was added and stirring was continued for 3 hours. The reactionmixture was filtered over Celite (15 g) and washed with ethyl acetate(3×20 mL). The filtrate was concentrated under vacuum to give an oilwhich was dissolved in isopropyl alcohol (2.6 L) and treated with sodiumiodide (32.26 g, 0.215 mol). The mixture was heated to reflux to afforda clear solution which was cooled to room temperature and then to 5° C.for 2 hours. The resulting white precipitate was filtered and washedwith isopropanol and dried under vacuum at 40° C. to a constant weightof 81.55 g, 69.2%. The product may be further purified byrecrystallization from isopropanol.

¹ H NMR (300 MHZ, D₂ O): (ppm) 1.00 (d, 3H, J=7.4 Hz), 1.05 (t, 3H,J=7.2 Hz), 1.68-2.10 (m,6H), 2.47 (t,2H, J=7.4 Hz PhCH₂), 2.94 (t,0.7H), 3.11 (t, 0.3H), 3.20-3.28 (m, 1H), 3.37-3.42 (m, 2H), 3.93 (q,2H, J=7.1 Hz), 4.00-4.04 (dd, 1H), 7.05-7.19 (m, 5H, Ar).

¹³ C NMR (75 MHZ, DMSO-_(d6)): 171.2, 173.4, 174.0 (C═O), 141.5/141.9(Ar), 128.1, 128.2, 128.3 (Ar), 125.5 (Ar), 58.4/58.6, 60.9/61.5, 59.7(CH₃ CH₂ O), 52.3, 45.7, 34.7, 22.1, 29.1, 31.1, 18.5 (CH₃), 14.0 (CH₃CH₂ O).

IR (KBr): (cm⁻¹) 3426 (NH), 2874-2966 (Ar), 1730 (C═O ester), 1684(C═O), 1646 (C═O).

EXAMPLE 2 Sodium Enalapril

Sodium enalapril.sodium iodide complex (100 g, 0.182 mole) andtetramethylammonium chloride (20 g, 0.182 mole) were ground to a powderand transferred with stirring to a flask containing 1000 mL toluene. Tothe mixture was added 40 mL water and stirring was continued for 15minutes. Water was removed by azeotropic distillation under vacuum(Dean-Stark apparatus). The resulting heterogeneous mixture was cooledto 15° C. and filtered over a bed of Celite. Solvent was removed underreduced pressure from the clear filtrate followed by drying of theresulting oil under high vacuum at 55° C. for 24 hours to afford 72 g(99.4%) of a foam.

As many changes can be made to the embodiments and examples as would beunderstood by persons skilled in the art without departing from thescope of the invention, it is understood that all material containedherein be interpreted as illustrative of the invention and not in alimiting sense.

The Embodiment of the Invention in which an Exclusive Property orPrivilege is claimed are as follows:
 1. The Complex ##STR4##